Peptide deformylase inhibitors

ABSTRACT

Novel PDF inhibitors and novel methods for their use are provided.

FIELD OF THE INVENTION

The present invention relates to the use of novel antibacterialcompounds, and pharmaceutical compositions containing these compounds aspeptide deformylase inhibitors.

BACKGROUND OF THE INVENTION

Bacterial initiator methionyl tRNA is modified by methionyl tRNAformyltransferase (FMT) to produce formyl-methionyl tRNA. The formylmethionine (f-met) is then incorporated at the N-termini of newlysynthesized polypeptides. Polypeptide deformylase (PDF or Def) thendeformylates primary translation products to produce N-methionylpolypeptides. Most intracellular proteins are further processed bymethionine amino peptidase (MAP) to yield the mature peptide and freemethionine, which is recycled. PDF and MAP are both essential forbacterial growth, and PDF is required for MAP activity. This series ofreactions is referred to as the methionine cycle (FIG. 1).

To date, polypeptide deformylase homologous genes have been found inbacteria, in chloroplast-containing plants, in mice and in human. Theplant proteins are nuclear encoded but appear to carry a chloroplastlocalisation signal. This is consistent with the observation thatchloroplast RNA and protein synthesis processes are highly similar tothose of eubacteria. While there is limited information on proteinexpression of mammalian PDF gene homologs (Bayer Aktiengesellschaft,Pat. WO2001/42431), no functional role for such proteins has beendemonstrated to date (Meinnel, T., Parasitology Today 16(4), 165-168,2000).

Polypeptide deformylase is found in all eubacteria for which highcoverage genomic sequence information is available. Sequence diversityamong PDF homologs is high, with as little as 20% identity betweendistantly related sequences. However, conservation around the activesite is very high, with several completely conserved residues, includingone cysteine and two histidines which are required to coordinate theactive site metal (Meinnel, T. et al., J. Mol. Biol. 267, 749-761,1997).

PDF is recognized to be an attractive antibacterial target, as thisenzyme has been demonstrated to be essential for bacterial growth invitro (Mazel, D. et al., EMBO J. 13 (4), 914-923, 1994), is not believedto be involved in eukaryotic protein synthesis (Rajagopalan et al., J.Am. Chem. Soc. 119, 12418-12419, 1997), and is universally conserved inprokaryotes (Kozak, M., Microbiol. Rev. 47, 1-45, 1983). Therefore PDFinhibitors can potentially serve as broad spectrum antibacterial agents.

SUMMARY OF THE INVENTION

The present invention involves novel antibacterial compounds representedby Formula (1) hereinbelow and their use as PDF inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention, there is provided a compound offormula (1):

wherein:R is selected from the group consisting of:

-   -   C₂₋₆ alkyl (optionally substituted by alkoxy, halogen, or C₁₋₃        alkylsulfanyl);    -   C₂₋₆ alkenyl (optionally substituted by alkoxy, halogen, or C₁₋₃        alkylsulfanyl);    -   C₂₋₆ alkynyl (optionally substituted by alkoxy, halogen, or C₁₋₃        alkylsulfanyl);    -   (CH₂)_(n)—C₃₋₆ carbocycle (optionally substituted by alkoxy,        halogen, or C₁₋₃ alkylsulfanyl); and (CH₂)_(n)—R2, wherein R2 is        selected from the group consisting of phenyl, furan, benzofuran,        thiophene, benzothiophene, tetrahydrofuran, tetrahydropyran,        dioxane, 1,4-benzodioxane or benzo[1,3]dioxole; R2 is optionally        substituted by one or more substituent selected from Cl, Br, I,        C₁₋₃ alkyl (optionally substituted by one to three F) and C₁₋₂        alkoxy (optionally substituted by one to three F);        R1 is selected from the group consisting of aryl and heteroaryl;        Y represents O, CH₂ or a covalent bond; and        n is an integer from 0 to 2;        or a salt, solvate, or physiologically functional derivative        thereof.

In this invention the most preferred absolute configuration of compoundsof the formula (1) is indicated below:

As used herein, the term “alkyl” refers to a straight or branched chainsaturated hydrocarbon radical. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like.

As used herein, the term “substituted alkyl” refers to a straight orbranched chain saturated hydrocarbon radical, optionally substitutedwith substituents selected from the group that includes C₁₋₃ alkyl(optionally substituted by one to three fluorines), C₂₋₃ alkenyl, C₂₋₃alkynyl, C₁₋₂ alkoxy (optionally substituted by one to three fluorines),sulfanyl, sulfinyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino,carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy,heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, ureido, nitro,cyano and halogen, multiple degrees of substitution being allowed.

As used herein, the term “alkenyl” refers to a straight or branchedchain hydrocarbon radical having at least one carbon-carbon double bond.Examples of “alkenyl” as used herein include, but are not limited to,ethenyl and propenyl.

As used herein, the term “substituted alkenyl” refers to a straight orbranched chain hydrocarbon radical having at least one carbon-carbondouble bond, optionally substituted with substituents selected from thegroup which includes C₁₋₃ alkyl (optionally substituted by one to threeF), amino, aryl, cyano and halogen, multiple degrees of substitutionbeing allowed.

As used herein, the term “alkynyl” refers to a straight or branchedchain hydrocarbon radical having at least one carbon-carbon triple bond.Examples of “alkynyl” as used herein include, but are not limited to,acetylenyl and 1-propynyl.

As used herein, the term “substituted alkynyl” refers to a straight orbranched chain hydrocarbon radical having at least one carbon-carbontriple bond, optionally substituted with substituents selected from thegroup which includes C₁₋₃ alkyl (optionally substituted by one to threeF), amino, aryl and halogen, multiple degrees of substitution beingallowed.

As used herein, the term “halogen” refers to fluorine (F), chlorine(Cl), bromine (Br), or iodine (I), and “halo” refers to the halogenradicals fluoro, chloro, bromo and iodo.

As used herein, the term “carbocycle” refers to a non-aromatic cyclichydrocarbon radical having from three to seven carbon atoms. Forcarbocycles with five- to seven-membered rings, a ring double bond isallowed. Exemplary “carbocycle” groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, andcycloheptyl.

As used herein, the term “substituted carbocycle” refers to anon-aromatic cyclic hydrocarbon radical having from three to sevencarbon atoms, and which is optionally substituted with substituentsselected from the group which includes C₁₋₃ alkyl (optionallysubstituted by one to three F), C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₂ alkoxy(optionally substituted by one to three F), sulfanyl, sulfinyl,sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy,aminocarbonyl, aryl, aryloxy, heteroaryl, heterocyclic, aminosulfonyl,sulfonylamino, carboxyamide, nitro, ureido, cyano and halogen, multipledegrees of substitution being allowed. For carbocycles with five- toseven-membered rings, a ring double bond is allowed.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring fused to oneor more optionally substituted benzene rings to form a ring system.Exemplary optional substituents include C₁₋₃ substituted alkyl, C₂₋₃substituted alkenyl, C₂₋₃ substituted alkynyl, heteroaryl, heterocyclic,aryl, C₁₋₃ alkoxy (optionally substituted by one to three F), aryloxy,aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino,carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino,nitro, cyano, halogen, or ureido, multiple degrees of substitution beingallowed. Such a ring or ring system may be optionally fused to one ormore optionally substituted aryl rings (including benzene rings),carbocycle rings or heterocyclic rings. Examples of “aryl” groupsinclude, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl,biphenyl, indanyl, anthracyl or phenanthryl, as well as substitutedderivatives thereof.

As used herein, the term “heteroaryl” refers to an optionallysubstituted monocyclic five to six membered aromatic ring containing oneor more heteroatomic substitutions selected from S, SO, SO₂, O, N, orN-oxide, or to such an aromatic ring fused to one or more optionallysubstituted rings, such as heteroaryl rings, aryl rings, heterocyclicrings, or carbocycle rings (e.g., a bicyclic or tricyclic ring system).Examples of optional substituents are selected from the group whichincludes C₁₋₃ substituted alkyl, C₂₋₃ substituted alkenyl, C₂₋₃substituted alkynyl, heteroaryl, heterocyclic, aryl, C₁₋₃ alkoxy(optionally substituted by one to three F), aryloxy, aralkoxy, acyl,aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl,sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide,aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano,halogen or ureido, multiple degrees of substitution being allowed.Examples of “heteroaryl” groups used herein include, but are not limitedto, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzothiophenyl,benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1,4]dioxanyl,benzofuranyl, 9H-α-carbolinyl, cinnolinyl,2,3-dihydro-[1,4]dioxino[2,3-b]-pyridinyl, furanyl,furo[2,3-b]pyridinyl, imidazolyl, imidazolidinyl, imidazopyridinyl,isoxazolyl, isothiazolyl, isoquinolinyl, indolyl, indazolyl,indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl,phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl,pyrazolyl, pyridyl, pyrazolopyrimidinyl, pyrazolopyridinyl,pyrrolizinyl, pyridazyl, pyrazinyl, pyrimidyl,4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]-quinolinyl, quinoxalinyl,quinazolinyl, quinolinyl, quinolizinyl, thiophenyl, triazolyl,triazinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl,thiazolyl, thiazolidinyl, and substituted versions thereof.

As used herein, the term “alkoxy” refers to the group —OR_(a), whereR_(a) is alkyl as defined above. Exemplary alkoxy groups useful in thepresent invention include, but are not limited to, methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, and t-butoxy.

As used herein the term “aralkoxy” refers to the group —OR_(a)R_(b),where R_(a) is alkyl and R_(b) is aryl as defined above.

As used herein the term “aryloxy” refers to the group —OR_(a), whereR_(a) is aryl as defined above.

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “sulfanyl” refers to the group —SR_(a), whereR_(a) is substituted alkyl, substituted carbocycle, aryl, heteroaryl orheterocyclic, as defined above.

As used herein, the term “sulfinyl” refers to the group —S(O)R_(a),where R_(a) is substituted alkyl, substituted carbocycle, aryl,heteroaryl or heterocyclic, as defined above.

As used herein, the term “sulfonyl” refers to the group —S(O)_(n)R_(a),where R_(a) is substituted alkyl, substituted carbocycle, aryl,heteroaryl or heterocyclic, as defined above.

As used herein, the term “oxo” refers to the group ═O.

As used herein, the term “hydroxy” refers to the group —OH.

As used herein, the term “amino” refers to the group —NH₂. The aminogroup is optionally substituted by substituted alkyl, substitutedcarbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term “cyano” refers to the group —CN.

As used herein, the term “aminosulfonyl” refers to the group—S(O)_(n)HH₂. The aminosulfonyl group is optionally substituted bysubstituted alkyl, substituted carbocycle, aryl, heteroaryl orheterocyclic, as defined above.

As used herein, the term “sulfonylamino” refers to the group—NHS(O)₂R_(a) where R_(a) is substituted alkyl, substituted carbocycle,aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term “carboxyamide” refers to the group —NHC(O)R_(a)where R_(a) is substituted alkyl, substituted carbocycle, aryl,heteroaryl or heterocyclic, as defined above.

As used herein, the term “carboxy” refers to the group —C(O)OH. Thecarboxy group is optionally substituted by substituted alkyl,substituted carbocycle, aryl, heteroaryl or heterocyclic, as definedabove.

As used herein, the term “aminocarbonyl” refers to the group —C(O)NH₂.The aminocarbonyl group is optionally substituted by substituted alkyl,substituted carbocycle, aryl, heteroaryl or heterocyclic, as definedabove.

As used herein, the term “ureido” refers to the group —NHC(O)NHR_(a)wherein R_(a) is hydrogen, alkyl, carbocycle or aryl as defined above.

As used herein, the term “guanidino” refers to the group —NHC(═NH)NH₂.

As used herein, the term “acyl” refers to the group —C(O)R_(a), whereR_(a) is alkyl, carbocycle, or heterocyclic as defined herein.

As used herein, the term “aroyl” refers to the group —C(O)R_(a), whereR_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group —C(O)R_(a),where R_(a) is heteroaryl as defined herein.

As used herein, the term “acyloxy” refers to the group —OC(O)R_(a),where R_(a) is alkyl, carbocycle, or heterocyclic as defined herein.

As used herein, the term “aroyloxy” refers to the group —OC(O)R_(a),where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the group—OC(O)R_(a), where R_(a) is heteroaryl as defined herein.

Also included in the present invention are pharmaceutically acceptablesalts and complexes, such as the hydrochloride, hydrobromide andtrifluoroacetate salts and the sodium, potassium and magnesium salts.The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeforms. All of these compounds and diastereomers are contemplated to bewithin the scope of the present invention.

Preferred compounds useful in the present invention are selected fromthe group consisting of:

-   Quinoline-8-carboxylic acid    ((R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino)--methyl)-amide.-   1,2,3,4-Tetrahydro-quinoline-8-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   Benzofuran-2-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   Quinoline-6-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   1,2,3,4-Tetrahydro-quinoline-6-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoyl]amino}-methyl)-amide.-   7-Methoxy-benzofuran-2-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   5-Methoxy-benzofuran-2-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoyl    amino}-methyl)-amide.-   5-Trifluoromethyl-furan-2-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   3,4-Difluoro-N-({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-benzamide.-   2,3-Difluoro-N-({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-benzamide.-   [1,8]Naphthyridine-2-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   3-Methyl-benzofuran-2-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   Benzo[1,3]dioxole-5-carboxylic acid    ({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.-   Benzofuran-2-carboxylic acid    {[(R)-2-cyclopentylmethyl-3-(formyl-hydroxy-amino)-propanoylamino]-methyl}-amide.-   Benzofuran-2-carboxylic acid    ({(R)-7,7,7-trifluoro-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.

General Synthetic Sequence

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes, which aremerely illustrative of the methods by which the compounds of theinvention may be prepared and are not intended to limit the scope of theinvention as defined in the appended claims.

The present invention provides compounds of Formula (1) that can beprepared from the common racemic intermediate (8), or common chiralintermediates (17) and (25).

As shown in Scheme 1, intermediate (8) can be prepared by reacting themono-substituted dialkyl malonate (2) with a base, such as potassiumhydroxide, in an appropriate solvent, such as ethanol/water, to affordthe mono-acid (3). Coupling of (3) with O-benzylhydroxylamine in thepresence of a coupling reagent, such as1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI),and a base, such as 4-dimethylaminopyridine (DMAP), in an appropriatesolvent, such as dichloromethane, gives the amide (4). Reduction of theester functionality of compound (4) with a reducing agent, such aslithium borohydride, in an appropriate solvent, such as tetrahydrofuran,at room temperature provides the alcohol (5). Treatment of the alcohol(5) under Mitsunobu conditions affords the lactam (6). The sametransformation may be achieved by treating (5) with triphenylphosphine,carbon tetrachloride and a base, such as triethylamine, to obtain (6).Hydrolysis of the lactam (6) using, for example, lithium hydroxide in anappropriate solvent mixture, such as THF-H₂O-MeOH, gives acid (7).Formylation of the amine group of (7) is achieved using formic acid andacetic anhydride in a solvent, such as dichloromethane, to provide theformylated compound (8).

Any racemates can be resolved at the level of any intermediate duringthe synthesis or at the level of the final product using, for example, achiral chromatography method, to provide compound (8) in each of twoenantiomeric forms.

Alternatively, an enantiomer of intermediate (8), such as (17) in Scheme2 or (25) in Scheme 3, can be prepared by reacting an appropriate acidchloride (9) with a chiral agent, such as Evans' chiral oxazolidinone,in the presence of a base, such as n-butyl lithium, to afford the chiralintermediate (10) in Scheme 2 or (18) in Scheme 3. Treatment of thecompound (10) or (18) with a base, such as diisopropylethylamine, in thepresence of a chelating agent, such as titanium tetrachloride, in asolvent, such as tetrahydrofuran, followed by addition of anelectrophile, such as benzyloxymethylchloride, provides either of twochiral compounds (11) or (19), depending on the selection of chiralauxiliary.

Conversion of compound (11) or (19) to the corresponding hydroxyacid(13) or (21) can be achieved by a sequence comprising oxidative cleavageof the chiral oxazolidinone, using, for example H₂O₂ and lithiumhydroxide, to the respective intermediates (12) or (20), followed byhydrogenolysis. Coupling of the acid (13) or (21) with benzyloxyamine inthe presence of coupling agents, such as EDCI/DMAP, yields the amides(14) or (22), respectively. These can be cyclized to the azetidin-2-ones(15) or (23) using Mitsunobu conditions or a combination oftriphenylphosphine/carbon tetrachloride/triethylamine. Hydrolysis of theazetidin-2-one (15) or (23), using for example lithium hydroxide, in anappropriate solvent, gives the corresponding acid (16) or (24),respectively. Conversion of compound (16) or (24) to the formate (17) or(25) can be achieved using an appropriate formylating agent, such asformic acid/acetic anhydride or methyl formate, in an appropriatesolvent, such as dichloromethane.

As shown in Scheme 4, coupling of carboxylic acid R1COOH (26) withglycinamide hydrochloride, using conditions such as DMAP/EDCI orEDCI/HOAt/NMM, provides the N-carbamoylmethyl amide (27). Rearrangementof (27) using [bis(trifluoroacetoxy)iodo]-benzene (PIFA) in a solventsuch as a mixture of acetonitrile and water, followed by treatment withan cid such as hydrochloric acid, affords the N-aminomethyl amide as thecorresponding salt (28). Coupling of (28) with acid (8), usingconditions such as DMAP/EDCI or EDCI/HOAt/NMM, provides (29), which canbe debenzylated by hydrogenation using a catalyst, such as 10% Pd/C, inan appropriate solvent, such as ethanol, to give the desired compound(1). Similarly, coupling of the chiral acid (17) or (25) with (28)provides the corresponding product (30) or (31). Hydrogenolysis of thebenzyl group gives the final desired compound (32) or (33).

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification.

-   -   Hz (Hertz); TLC (thin layer chromatography);    -   Tr (retention time); RP (reverse phase);    -   MeOH (methanol); i-PrOH (isopropanol);    -   EtOH (ethanol); TEA (triethylamine);    -   TFA (trifluoroacetic acid); THF (tetrahydrofuran);    -   DMSO (dimethylsulfoxide); AcOEt or EtOAc (ethyl acetate);    -   DCM (dichloromethane); DMF (N,N-dimethylformamide);    -   CDI (1,1-carbonyldiimidazole); HOAc (acetic acid);    -   HOSu (N-hydroxysuccinimide); Ac (acetyl);    -   HOBT (1-hydroxybenzotriazole); BOC (tert-butyloxycarbonyl);    -   mCPBA (meta-chloroperbenzoic acid); FMOC        (9-fluorenylmethoxycarbonyl);    -   DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);    -   NMM (N-methyl morpholine); HOAt (1-hydroxy-7-azabenzotriazole);    -   DMAP (4-dimethylaminopyridine); Bn (benzyl);    -   TBAF (tetra-n-butylammonium fluoride);    -   HPLC (high pressure liquid chromatography);    -   BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);    -   EDCI (1-ethyl-3-[3-dimethylaminopropyl]carbodiimide        hydrochloride);    -   HBTU (O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate);    -   PIFA ([bis(trifluoroacetoxy)iodo]-benzene).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at room temperature unlessotherwise noted, and all solvents are highest available purity unlessotherwise indicated.

¹H NMR (hereinafter also “NMR”) spectra were recorded on a VarianVXR-300, a Varian Unity-300, a Varian Unity-400 instrument, a BruckerAVANCE-400, a General Electric QE-300 or a Bruker AM 400 spectrometer.Chemical shifts are expressed in parts per million (ppm, δ units).Coupling constants are in units of hertz (Hz). Splitting patternsdescribe apparent multiplicities and are designated as s (singlet), d(doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br(broad).

Mass spectra were run on an open access LC-MS system using electrosprayionization. LC conditions: 4.5% to 90% CH₃CN (0.02% TFA) in 3.2 min witha 0.4 min hold and 1.4 min re-equilibration; detection by MS, UV at 214nm, and a light scattering detector (ELS). Column: 1×40 mm Aquasil(C18).

For preparative (prep) hplc; ca 50 mg of the final products wereinjected in 500 uL of DMSO onto a 50×20 mm I. D. YMC CombiPrep ODS-Acolumn at 20 mL/min with a 10 min gradient from 10% CH₃CN (0.1% TFA) to90% CH₃CN (0.1% TFA) in H₂O (0.1% TFA) and a 2 min hold. Flashchromatography was run over Merck Silica gel 60 (230-400 mesh).

Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometerusing a 1-mm NaCl cell. Most of the reactions were monitored bythin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid orp-anisaldehyde solution.

The following synthetic schemes are merely illustrative of the methodsby which the compounds of the invention may be prepared and are notintended to limit the scope of the invention as defined in the appendedclaims.

The compounds disclosed in Examples 2 to 32 were prepared following thegeneral procedures described in Example 1. The compounds disclosed inExamples 34 to 47 were prepared following the general proceduresdescribed in Example 33.

Preparation 1 (4S)-Benzyl-3-heptanoyl-oxazolidin-2-one

To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (3.3 g, 18.6 mmol) inTHF (50 mL) at −78° C. was added dropwise n-BuLi (7.4 mL, 2.5M solutionin hexane, 18.6 mmol). After stirring for 30 min at the sametemperature, the reaction mixture was then treated with heptanoylchloride (2.76 g, 18.6 mmol). The reaction mixture was stirred andallowed to warm to 10° C. over 5 h, and then quenched with saturatedaqueous NH₄Cl solution (100 mL). The aqueous layer was extracted withEtOAc (100 mL×2). The combined organic layers were washed with brine,and dried over MgSO₄. Removal of the solvent under reduced pressureyielded the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.22 (m, 5H),4.69 (m, 1H), 4.19 (m, 2H), 3.31 (dd, J=13.4, 3.3 Hz, 1H), 2.95 (m, 2H),2.79 (dd, J=13.4, 9.7 Hz, 11H), 1.71 (m, 2H), 1.42-1.32 (m, 6H), 0.92(t, J=6.8 Hz, 3H). MH+290.

Preparation 2(4S)-Benzyl-3-[(2R)-benzyloxymethylheptanoyl]oxazolidin-2-one

To a solution of (S)-4-benzyl-3-heptanoyloxazolidin-2-one (4.63 g, 16.02mmol) and titanium (IV) chloride (1.9 mL, 16.82 mmol) in dichloromethane(55 mL) at 0° C. was added dropwise diisopropylethylamine (3.1 mL, 17.62mmol). After stirring at 0° C. for 1 hour, the resulting titaniumenolate was then reacted with benzylchloromethyl ether (TCI-America, 4.9mL, 32.04 mmol) at 0° C. for 6 h. The reaction mixture was then quenchedwith water (100 mL). The aqueous layer was extracted withdichloromethane (100 mL×2). The organic extracts were washed with brine,and dried over MgSO₄. After removing the solvent under reduced pressure,purification by flash column chromatography using an eluting system ofhexane/EtOAc (5:1) yielded the title compound. ¹H NMR (400 MHz, CDCl₃) δ7.38-7.21 (m, 10H), 4.74 (m, 1H), 4.57 (m, 2H), 4.28-4.13 (m, 3H), 3.82(t, J=8.7 Hz, 1H), 3.68 (dd, J=9.0, 4.9 Hz, 11H), 3.25 (dd, J=13.5, 3.1Hz, 1H), 2.71 (dd, J=13.5, 9.3 Hz, 1H), 1.74 (m, 1H), 1.54 (m, 1H),1.31-1.28 (m, 6H), 0.89 (t, J=6.7 Hz, 3H). MH+410.

Preparation 3 (3R)-Benzyloxy-2-pentylpropionic acid

A 0.05 M solution of(S)-4-benzyl-3-[(R)-2-benzyloxymethylheptanoyl]oxazolidin-2-one (2.0 g,4.89 mmol) in a 3:1 mixture of THF and H₂O was treated with 30% H₂O₂(4.5 L, 39.12 mmol), followed by LiOH (0.48 g, 9.78 mmol) at 0° C. Theresulting mixture was stirred and allowed to warn to room temperatureovernight. THF was then removed under vacuum. The residue was washedwith dichloromethane (50 mL×2) to remove (S)-4-benzyloxazolidin-2-one.The desired product was isolated by EtOAc extraction of the acidified(pH 1-2) aqueous phase. No further purification was required. Standingunder high vacuum yielded the title compound. ¹H NMR (400 MHz, CHCl₃) δ11.1 (br s, 1H), 7.36 (m, 5H), 4.57 (s, 2H), 3.69 (m, 1H), 3.58 (dd,J=9.2, 5.2 Hz, 1H), 2.74 (m, 1H), 1.66 (m, 1H), 1.54 (m, 1H), 1.34-1.30(m, 6H), 0.90 (t, J=6.7 Hz, 3H). MH+251.

Preparation 4 3-Hydroxy-(2R)-pentylpropionic acid

To a solution of (R)-3-benzyloxy-2-pentyl-propionic acid (1.54 g, 6.16mmol) in EtOH (100 mL) was added 10% Pd/C (310 mg). The reaction mixturewas subjected to hydrogenation overnight at room temperature. After thereaction was completed, the reaction mixture was filtered through a padof Celite, and washed with EtOH (50 mL×3). Removal of the solventprovided the title compound. No further purification was required. ¹HNMR (400 MHz, CHCl₃) δ 6.30 (br s, 1H), 3.81 (d, J=5.4 Hz, 2H), 2.64 (m,1H), 1.69 (m, 1H), 1.56 (m, 1H), 1.41-1.27 (m, 6H), 0.91 (t, J=7.7 Hz,3H). MH+161.

Preparation 5 N-Benzyloxy-3-hydroxy-(2R)-pentylpropionamide

To a mixture of (R)-3-hydroxy-2-pentylpropionic acid (0.92 g, 5.75mmol), O-benzyl hydroxylamine hydrochloride (0.92 g, 5.75 mmol) and4-(dimethylamino)pyridine (1.41 g, 11.50 mmol) in dichloromethane (25mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (1.11 g, 5.75 mmol). After stirring at room temperatureovernight, the reaction was then quenched with 1N aqueous HCl solution(25 mL) and extracted using dichloromethane (25 mL×2). The organicextracts were washed with water, brine, and dried over MgSO₄. Removal ofthe solvent under reduced pressure yielded the title compound. ¹H NMR(400 MHz, CHCl₃) δ 9.22 (br s, 1H), 7.41-7.28 (m, 5H), 4.89 (q, J=10.6Hz, 2H), 3.70-3.37 (m, 3H), 2.17 (m, 1H), 1.54 (br s, 1H), 1.27 (m, 6H),0.88 (t, J=6.9 Hz, 3H). MH+266.

Preparation 6 1-benzyloxy-(3R)-pentyl-azetidin-2-one

To a mixture of (R)—N-benzyloxy-3-hydroxy-2-pentylpropionamide (1.41 g,5.32 mmol) and triphenylphosphine (1.68 g, 6.39 mmol) in THF (53 mL) wasadded dropwise diethyl azodicarboxylate (1.1 mL, 6.39 mmol) at 0° C. Thereaction mixture was stirred and allowed to warm to room temperatureovernight. The reaction was then quenched with water (50 mL). Theaqueous layer was extracted with EtOAc (50 mL×2). The combined organiclayers were washed with brine, and dried over MgSO₄. After removing thesolvent under vacuum, the residue was purified by flash columnchromatography (hex:EtOAc 5/1) to provide the title compound. ¹H NMR(400 MHz, CHCl₃) δ 7.35-7.25 (m, 5H), 4.87 (s, 2H), 3.28 (t, J=4.85 Hx,1H), 2.84 (q, J=2.35 Hz, 1H), 2.77 (m, 1H), 1.62 (m, 1H), 1.36 (m, 1H),1.25-1.16 (m, 6H), 0.88 (t, J=6.9 Hz, 3H). MH+248.

Preparation 7 3-benzyloxyamino-(2R)-pentylpropionic acid

To a mixture of (R)-1-benzyloxy-3-pentylazetidin-2-one (0.96 g, 3.89mmol) in a mixture of THF-H₂O-MeOH (50 mL, 3:1:1 v/v) was added lithiumhydroxide monohydrate (1.91 g, 38.9 mmol). After stirring at roomtemperature overnight, water (25 mL) was added to the mixture. Thesolution was acidified to pH 5-6 with 3N aqueous HCl solution. It wasextracted with EtOAc (50 mL×2). The combined organic layers were driedover MgSO₄. Removal of the solvent under vacuum provided the titlecompound. ¹H NMR (400 MHz, CHCl₃) δ 9.80 (br s, 1H), 7.37 (m, 5H), 4.75(m, 2H), 3.14 (m, 2H), 2.74 (m, 1H), 1.70 (m, 1H), 1.53 (m, 1H),1.38-1.25 (m, 6H), 0.91 (t, J=6.8 Hz, 3H). MH+266.

Preparation 8 (2R)-[(benzyloxyformylamino)methyl]heptanoic acid

To a cold solution of (R)-3-Benzyloxyamino-2-pentylpropionic acid (1.03g, 3.89 mmol) in HCO₂H (19 mL) and dichloromethane (19 mL) at 0° C. wasadded acetic anhydride (3.9 mL, 41.2 mmol). The mixture was stirred at0° C. for 3 hours. The volatiles were removed by evaporation undervacuum. Dichloromethane (50 mL) was added to it. It was washed withbrine (50 mL×2), and dried over MgSO₄. Filtration and evaporation undervacuum provided the title compound. ¹H NMR (400 MHz, CHCl₃) δ 8.07 (brs, 1H), 7.29 (m, 5H), 4.91-4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H),1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+294.

Preparation 9 N-Carbamoylmethyl-quinoline-8-carboxamide

To a mixture of quinoline-8-carboxylic acid (3.45 mmol), glycinamidehydrochloride (3.45 mmol), NMM (41.43 mmol) and HOAt (4.14 mmol) in DMF(17 mL) at room temperature was added1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (4.14mmol). After stirring at room temperature overnight, the reactionmixture was purified by HPLC to afford the title compound as a whitesolid. MH+230.

Preparation 10 N-Aminomethyl-quinoline-8-carboxamide hydrochloride

PIFA (0.60 mmol) was dissolved in acetonitrile (1.5 mL). To thissolution deionized water (1.5 mL) was added. FinallyN-carbamoylmethyl-quinoline-8-carboxamide (0.60 mmol) was added, and thereaction mixture was allowed to stir at room temperature overnight. Thereaction mixture was diluted with 1N HCl (15 mL) and was washed twicewith ether (20 mL×2). The aqueous layer was concentrated under reducedpressure. The resulting residue (white solid) was directly used in thenext step.

Preparation 11 Quinoline-8-carboxylic acid((R)-2-[(formyl-benzyloxy-amino)-methyl]-heptanoylamino}-methyl)-amide

To a mixture of (R)-2-[(benzyloxyformyl-amino)methyl]heptanoic acid(0.535 mmol), N-aminomethyl-quinoline-8-carboxamide hydrochloride (0.535mmol), NMM (5.35 mmol) and HOAt (0.642 mmol) in DMF (6 mL) at roomtemperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimidehydrochloride (0.642 mmol). After stirring at room temperatureovernight, the reaction mixture was then purified by HPLC to afford thetitle compound as a white solid. MH+477.

Example 1 Quinoline-8-carboxylic acid((R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

To a solution of quinoline-8-carboxylic acid((R)-2-[(formyl-benzyloxy-amino)-methyl]-heptanoylamino}-methyl)-amide(0.260 mmol) in EtOH (10 mL) was added 10% Pd/C (22 mg). The reactionmixture was subjected to hydrogenation overnight at room temperature.The reaction mixture was then filtered through a pad of Celite, andwashed with EtOH (10 mL×2). Removal of the solvent provided the crudeproduct, which was further purified by HPLC to yield the title compound.¹H NMR (400 MHz, CD₃OD) δ 9.03 (d, 1H, J=4.2 Hz), 8.70 (d, 1H, J=7.3Hz), 8.48 (d, 1H, J=8.2 Hz), 8.16 (d, 1H, J=8.2 Hz), 7.88 (s, 1H), 7.74(t, 1H, J=7.7 Hz), 7.64 (dd, 1H, J=8.2, 4.2 Hz), 4.99 (ab quart, 2H),3.80-3.33 (m, 2H), 2.85 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.30-1.10(m, 6H), 0.64 (t, 3H, J=7.2 Hz). MH+387.

Example 2 1,2,3,4-Tetrahydro-quinoline-8-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

Purification by preparative HPLC yielded the title compound. ¹H NMR (400MHz, CD₃OD) δ 7.89 (s, 1H), 7.26 (d, 1H, J=8.0 Hz), 6.98 (d, 1H, J=7.1Hz), 6.44 (t, 1H, J=7.44 Hz), 4.70 (ab quart, 2H), 3.80-3.35 (m, 2H),3.35 (m, 2H), 2.82 (m, 1H), 2.77 (t, 2H, J=6.33 Hz), 1.88 (m, 2H),1.60-1.21 (m, 8H), 0.85 (t, 3H). MH+391.

Example 3 Benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

Purification by preparative HPLC yielded the title compound. ¹H NMR (400MHz, CD₃OD) δ 7.89 (s, 1H), 7.74 (d, 1H, J=7.8 Hz), 7.60 (d, 1H, J=8.4Hz), 7.54 (s, 1H), 7.48 (t, 1H), 7.34 (t, 1H), 4.79 (ab quart, 2H),3.89-3.40 (m, 2H), 2.86 (m, 1H), 1.50 (m, 1H), 1.35 (m, 1H), 1.30 (m,6H), 0.78 (t, 3H). MH+376.

Example 4 Quinoline-6-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 8.95 (d, 1H, J=2.9 Hz), 8.50 (m, 1H), 8.19(dd, 1H, J=8.9, 2.0 Hz), 8.11 (d, 1H, J=8.9 Hz), 7.91 (s, 1H), 7.64 (dd,1H, J=8.3, 4.2 Hz), 4.83 (ab quart, 2H), 3.87-3.30 (m, 2H), 2.89 (m,1H), 1.57 (m, 1H), 1.45 (m, 1H), 1.31-1.23 (m, 6H), 0.80 (t, 3H, J=6.8Hz). MH+387.

Example 5 1,2,3,4-Tetrahydro-quinoline-6-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

MH+391

Example 6 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoyl]amino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.36 (m, 2H), 6.89 (d, 1H, J=8.4Hz), 4.73 (ab quart, 2H, J=10.8, 3.7 Hz), 4.28 (m, 4H), 3.80-3.41 (m,2H), 2.82 (m, 1H), 1.54 (m, 1H), 1.44 (m, 1H), 1.24 (m, 6H), 0.85 (br t,3H). MH+394.

Example 7 7-Methoxy-benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.89 (s, 1H), 7.51 (s, 1H), 7.27 (m, 2H), 7.03(d, 1H, J=7.5 Hz), 4.78 (ab quart, 2H), 4.01 (s, 3H), 3.75 (m, 2H), 2.85(m, 1H), 1.55 (m, 1H), 1.44 (m, 1H), 1.27 (m, 6H), 0.77 (t, 3H, J=6.2Hz). MH+406.

Example 8 5-Methoxy-benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.89 (s, 1H), 7.49 (d, 1H, J=2.2 Hz), 7.48 (s,1H), 7.22 (d, 1H, J=2.5 Hz), 7.07 (dd, 1H, J=9.2, 2.6 Hz), 4.81 (abquart, 2H), 3.85 (s, 3H), 3.71 (m, 2H), 2.84 (m, 1H), 1.55 (m, 1H), 1.44(m, 1H), 1.28 (m, 6H), 0.79 (t, 3H, J=7.0 Hz). MH+406.

Example 9 3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.46 (s, 1H), 7.43 (d, 1H, J=8.3Hz), 7.00 (d, 1H, J=8.3 Hz), 4.73 (ab quart, 2H), 4.24 (m, 4H), 3.75 (m,2H), 2.83 (m, 1H), 2.21 (t, 2H), 1.55 (m, 1H), 1.45 (m, 1H), 1.27 (m,6H), 0.84 (br t, 3H). MH+408.

Example 10 5-Trifluoromethyl-furan-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.87 (s, 1H), 7.26 (d, 1H, J=3.8 Hz), 7.16 (d,1H, J=3.8 Hz), 4.75 (m, 2H), 3.76 (m, 2H), 2.84 (m, 1H), 1.55 (m, 1H),1.44 (m, 1H), 1.27 (m, 6H), 0.84 (t, 3H, J=6.5 Hz). MH+394.

Example 113,4-Difluoro-N-({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-benzamide

¹H NMR (400 MHz, CD₃OD) δ 7.87 (s, 1H), 7.81 (m, 1H), 7.79 (m, 1H), 7.41(m, 1H), 4.74 (ab quart, 2H), 3.77 (m, 2H), 2.85 (m, 1H), 1.55 (m, 1H),1.44 (m, 1H), 1.28 (m, 6H), 0.84 (t, 3H, J=6.8 Hz). MH+372.

Example 122,3-Difluoro-N-({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-benzamide

¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.48 (m, 2H), 7.27 (m, 1H), 4.75(ab quart, 2H), 3.75 (m, 2H), 2.86 (m, 1H), 1.55 (m, 1H), 1.44 (m, 1H),1.26 (m, 6H), 0.87 (t, 3H, J=6.5 Hz). MH+372.

Example 13 [1,8]Naphthyridine-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 9.18 (br s, 1H), 8.64 (d, 1H, J=8.3 Hz), 8.57(d, 1H, J=8.0 Hz), 8.37 (d, 1H, J=8.3 Hz), 7.77 (m, 1H), 4.85 (ab quart,2H), 3.76 (m, 2H), 2.84 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.25 (m,6H), 0.73 (t, 3H, J=6.9 Hz). MH+388.

Example 14 3-Methyl-benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.89 (s, 1H), 7.67 (t, 1H, J=7.5 Hz), 7.52 (d,1H, J=7.8 Hz), 7.46 (br s, 1H, J=7.2 Hz), 7.32 (br s, 1H, J=7.2 Hz),4.78 (ab quart, 2H), 3.70 (m, 2H), 2.85 (m, 1H), 2.59 (s, 3H), 1.55 (m,1H), 1.46 (m, 1H), 1.26 (m, 6H), 0.76 (br t, 3H). MH+390.

Example 15 Benzo[1,3]dioxole-5-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.44 (d, 1H, J=8.2 Hz), 7.32 (s,1H), 6.89 (d, 1H, J=8.2 Hz), 6.05 (s, 2H), 4.73 (ab quart, 2H), 3.76 (m,2H), 2.85 (m, 1H), 1.55 (m, 1H), 1.46 (m, 1H), 1.27 (m, 6H), 0.86 (t,3H, J=6.4 Hz). MH+380.

Example 16 Benzofuran-2-carboxylic acid{[(R)-2-cyclopentylmethyl-3-(formyl-hydroxy-amino)-propanoylamino]-methyl}-amide

¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.74 (d, 1H, J=7.8 Hz), 7.60 (d,1H, J=8.4 Hz), 7.54 (s, 1H), 7.48 (t, 1H, J=7.5 Hz), 7.34 (t, 1H, J=7.5Hz), 4.79 (ab quart, 2H), 3.89 (m, 2H), 2.86 (m, 1H), 1.85-1.37 (m,111H), 0.78 (m, 3H). MH+388.

Example 17 Benzofuran-2-carboxylic acid({(R)-7,7,7-trifluoro-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide

¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.74 (d, 1H, J=7.8 Hz), 7.60 (d,1H, J=8.4 Hz), 7.54 (s, 1H), 7.48 (t, 1H, J=7.5 Hz), 7.34 (t, 1H, J=7.5Hz), 4.79 (ab quart, 2H), 3.88 (m, 2H), 2.78 (m, 1H), 1.95 (m, 2H),1.50-1.21 (m, 6H). MH+430.

Compositions, Administration and Biological Assays

Compounds of Formula (1) and their pharmaceutically acceptable salts maybe administered in a standard manner for antibiotics, for exampleorally, parenterally, sublingually, dermally, transdermally, rectally,via inhalation or via buccal administration.

Compositions of Formula (1) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as syrups, tablets,capsules, creams and lozenges. A syrup formulation will generallyconsist of a suspension or solution of the compound or salt in a liquidcarrier for example, ethanol, peanut oil, olive oil, glycerine or waterwith a flavoring or coloring agent. Where the composition is in the formof a tablet, any pharmaceutical carrier routinely used for preparingsolid formulations may be used. Examples of such carriers includemagnesium stearate, terra alba, talc, gelatin, acacia, stearic acid,starch, lactose and sucrose. Where the composition is in the form of acapsule, any routine encapsulation is suitable, for example, using theaforementioned carriers in a hard gelatin capsule shell. Where thecomposition is in the form of a soft gelatin shell capsule, anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example, aqueous gums, celluloses,silicates or oils, and incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of acompound or salt in a sterile aqueous or non-aqueous carrier optionallycontaining a parenterally acceptable oil, for example, polyethyleneglycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

Typical compositions for inhalation are in the form of a solution,suspension or emulsion that may be administered as a dry powder or inthe form of an aerosol using a conventional propellant such asdichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (1) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample, polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogs.

Typical dermal and transdermal formulations comprise a conventionalaqueous or non-aqueous vehicle, for example, a cream, ointment, lotionor paste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer asingle dose.

Each dosage unit for oral administration contains suitably from 0.1 mgto 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosageunit for parenteral administration contains suitably from 0.1 mg to 100mg/Kg, of a compound of Formula (1) or a pharmaceutically acceptablesalt thereof calculated as the free acid. Each dosage unit forintranasal administration contains suitably 1-400 mg and preferably 10to 200 mg per person. A topical formulation contains suitably 0.01 to5.0% of a compound of Formula (1).

The daily dosage regimen for oral administration is suitably about 0.01mg/Kg to 40 mg/Kg of a compound of Formula (1) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for parenteral administration is suitably about 0.001 mg/Kg to40 mg/Kg of a compound of Formula (1) or a pharmaceutically acceptablesalt thereof calculated as the free acid. The daily dosage regimen forintranasal administration and oral inhalation is suitably about 10 toabout 500 mg/person. The active ingredient may be administered from 1 to6 times a day, sufficient to exhibit the desired activity.

No unacceptable toxicological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention.

The biological activity of the compounds of Formula (1) are demonstratedby the following test:

Biological Assay

S. aureus or E. coli PDF activity is measured at 25° C., using acontinuous enzyme-linked assay developed by Lazennec & Meinnel (“Formatedehydrogenase-coupled spectrophotometric assay of peptide deformylase”,Anal. Biochem. 1997, 244, pp. 180-182), with minor modifications. Thereaction mixture is contained in 50 uL with 50 mM potassium phosphatebuffer (pH 7.6), 15 mM NAD, 0.25 U formate dehydrogenase. The substratepeptide, f-Met-Ala-Ser, is included at the KM concentration. Thereaction is triggered with the addition of 10 nM Def1 enzyme, andabsorbance is monitored for 20 min at 340 nm.

Antimicrobial Activity Assay

Whole-cell antimicrobial activity was determined by broth microdilutionusing the National Committee for Clinical Laboratory Standards (NCCLS)recommended procedure, Document M7-A4, “Methods for DilutionSusceptibility Tests for Bacteria that Grow Aerobically” (incorporatedby reference herein). The compound was tested in serial two-folddilutions ranging from 0.06 to 64 mcg/ml. A panel of 12 strains wereevaluated in the assay. This panel consisted of the following laboratorystrains: Staphylococcus aureus Oxford, Staphylococcus aureus WCUH29,Enterococcus faecalis I, Enterococcus faecalis 7, Haemophilus influenzaeQ1, Haemophilus influenzae NEMC1, Moraxella catarrhalis 1502,Streptococcus pneumoniae 1629, Streptococcus pneumoniae N1387,Streptococcus pneumoniae N1387, E. coli 7623 (AcrABEFD+) and E. coli 120(AcrAB-). The minimum inhibitory concentration (MIC) was determined asthe lowest concentration of compound that inhibited visible growth. Amirror reader was used to assist in determining the MIC endpoint.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe area can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1. A compound according to Formula (1): In one aspect of the presentinvention, there is provided a compound of formula (1):

wherein: R is selected from the group consisting of: C₂₋₆ alkyl(optionally substituted by alkoxy, halogen, or C₁₋₃ alkylsulfanyl); C₂₋₆alkenyl (optionally substituted by alkoxy, halogen, or C₁₋₃alkylsulfanyl); C₂₋₆ alkynyl (optionally substituted by alkoxy, halogen,or C₁₋₃ alkylsulfanyl); (CH₂)_(n)—C₃₋₆ carbocycle (optionallysubstituted by alkoxy, halogen, or C₁₋₃ alkylsulfanyl); and(CH₂)_(n)—R2, wherein R2 is selected from the group consisting ofphenyl, furan, benzofuran, thiophene, benzothiophene, tetrahydrofuran,tetrahydropyran, dioxane, 1,4-benzodioxane or benzo[1,3]dioxole; R2 isoptionally substituted by one or more substituent selected from Cl, Br,I, C₁₋₃ alkyl (optionally substituted by one to three F) and C₁₋₂ alkoxy(optionally substituted by one to three F)}; R1 is selected from thegroup consisting of aryl and heteroaryl; Y represents O, CH₂ or acovalent bond; and n is an integer from 0 to 2; or a salt, solvate, orphysiologically functional derivative thereof.
 2. A compound accordingto claim 1, with the following absolute configuration:

or a salt, solvate or physiologically functional derivative thereof. 3.A compound according to claim 32 selected from the group consisting of:Quinoline-8-carboxylic acid((R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.1,2,3,4-Tetrahydro-quinoline-8-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.Benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.Quinoline-6-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.1,2,3,4-Tetrahydro-quinoline-6-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoyl]amino}-methyl)-amide:7-Methoxy-benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.5-Methoxy-benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.5-Trifluoromethyl-furan-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.3,4-Difluoro-N-({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-benzamide.2,3-Difluoro-N-({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-benzamide.[1,8]Naphthyridine-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.3-Methyl-benzofuran-2-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.Benzo[1,3]dioxole-5-carboxylic acid({(R)-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.Benzofuran-2-carboxylic acid{[(R)-2-cyclopentylmethyl-3-(formyl-hydroxy-amino)-propanoylamino]-methyl}-amide.Benzofuran-2-carboxylic acid({(R)-7,7,7-trifluoro-2-[(formyl-hydroxy-amino)-methyl]-heptanoylamino}-methyl)-amide.4. A method of treating a bacterial infection by administering to asubject in need of treatment a compound according to claim 1.